Nardilysin enhances ectodomain shedding of heparin-binding epidermal growth factor-like growth factor through activation of tumor necrosis factor-α-converting enzyme
Nardilysin enhances ectodomain shedding of heparin-binding epidermal growth factor-like growth factor through activation of tumor necrosis factor-α-converting enzyme
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DOI：
10.1074/jbc.m601316200
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发表时间：
2006-10-13
影响因子：
4.8
通讯作者：
Kita, Toru
中科院分区：
文献类型：
--
作者：
Nishi, Eiichiro;Hiraoka, Yoshinori;Kita, Toru
与表皮生长因子家族的其他成员一样，肝素结合表皮生长因子样生长因子（HB-EGF）作为一种跨膜蛋白合成，可以酶促脱落以释放可溶性生长因子。胞外结构域脱落对HB-EGF的生物学功能至关重要，并受到严格的调控。然而，诱导脱落的机制仍不清楚。我们最近已经鉴定了Nardilysin（N-精氨酸二元转化酶（NRDc）），M16家族的金属内肽酶，作为特异性结合HB-EGF的蛋白质（Nishi，E.，普拉，A.，医院，V，Elenius，K.，和Klagsbrun，M.（2001）EMBO J. 20，3342-3350）。在这里，我们表明NRDc增强HB-EGF的胞外域脱落。当在细胞中表达时，NRDc与肿瘤坏死因子-α-转化酶（TACE; ADAM 17）合作增强脱落。NRDc与TACE形成复合物，这是一个由佛波酯（胞外域脱落的一般激活剂）促进的过程。在肽裂解试验中，NRDc增强TACE诱导的HB-EGF裂解，表明与NRDc的相互作用增强TACE的催化活性。NRDc的金属内肽酶活性不是促进HB-EGF脱落所必需的。值得注意的是，RNA干扰引起的NRDc表达的减少伴随着HB-EGF胞外结构域脱落的减少。这些结果表明NRDc在HB-EGF胞外域脱落中的重要作用，并揭示了脱落是如何通过调节脱落酶活性来调节的。
Like other members of the epidermal growth factor family, heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a transmembrane protein that can be shed enzymatically to release a soluble growth factor. Ectodomain shedding is essential to the biological functions of HB-EGF and is strictly regulated. However, the mechanism that induces the shedding remains unclear. We have recently identified nardilysin (N-arginine dibasic convertase (NRDc)), a metalloendopeptidase of the M16 family, as a protein that specifically binds HB-EGF (Nishi, E., Prat, A., Hospital, V., Elenius, K., and Klagsbrun, M. (2001) EMBO J. 20, 3342-3350). Here, we show that NRDc enhances ectodomain shedding of HB-EGF. When expressed in cells, NRDc enhanced the shedding in cooperation with tumor necrosis factor-alpha-converting enzyme (TACE; ADAM17). NRDc formed a complex with TACE, a process promoted by phorbol esters, general activators of ectodomain shedding. NRDc enhanced TACE-induced HB-EGF cleavage in a peptide cleavage assay, indicating that the interaction with NRDc potentiates the catalytic activity of TACE. The metalloendopeptidase activity of NRDc was not required for the enhancement of HB-EGF shedding. Notably, a reduction in the expression of NRDc caused by RNA interference was accompanied by a decrease in ectodomain shedding of HB-EGF. These results indicate the essential role of NRDc in HB-EGF ectodomain shedding and reveal how the shedding is regulated by the modulation of sheddase activity.